G3139, an anti-Bcl-2 antisense oligomer that binds heparin- binding growth factors and collagen I, alters In vitro endothelial cell growth and tubular morphogenesis

C. A. Stein, Sijian Wu, Anatoliy M. Voskresenskiy, Jin Feng Zhou, Joongho Shin, Paul Miller, Naira Souleimanian, Luba Benimetskaya

Research output: Contribution to journalArticle

Abstract

Purpose: We examinedthe effects of G3139 on the interaction of heparin-binding proteins [e.g., fibroblast growth factor 2 (FGF2) andcollagen I] with endothelial cells. G3139 is an 18-mer phosphorothioate oligonucleotide targeted to the initiation codon region of the Bcl-2 mRNA. A randomized, prospective global phase III trial in advanced melanoma (GM301) has evaluated G3139 in combination with dacarbazine. However, the mechanism of action of G3139 is incompletely understood because it is unlikely that Bcl-2 silencing is the sole mechanism for chemo- sensitization in melanoma cells. Experimental Design: The ability of G3139 to interact with andprotect heparin-binding proteins was quantitated. The effects of G3139 on the binding of FGF2 to high-affinity cell surface receptors and the induction of cellular mitogenesis and tubular morphogenesis in HMEC-1 and human umbilical vascular endothelial cells were determined. Results: G3139 binds with picomolar affinity to collagen I. By replacing heparin, the drug can potentiate the binding of FGF2 to FGFR1 IIIc, and it protects FGF from oxidation and proteolysis. G3139 can increase endothelial cell mitogenesis and tubular morphogenesis of HMEC-1 cells in three-dimensional collagen gels, increases the mitogenesis of human umbilical vascular endothelial cells similarly, andinduces vessel sprouts in the rat aortic ring model. Conclusions: G3139 dramatically affects the behavior of endothelial cells. There may be a correlation between this observation andthe treatment interaction with lactate dehydrogenase ob- served clinically.

Original languageEnglish (US)
Pages (from-to)2797-2807
Number of pages11
JournalClinical Cancer Research
Volume15
Issue number8
DOIs
StatePublished - Apr 15 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'G3139, an anti-Bcl-2 antisense oligomer that binds heparin- binding growth factors and collagen I, alters In vitro endothelial cell growth and tubular morphogenesis'. Together they form a unique fingerprint.

  • Cite this